tbuckley/cabot-search huggingface dataset:
A translatable RNAi-driven gene therapy silences PMP22/Pmp22 genes and improves neuropathy in CMT1A mice
Authors: Marina Stavrou, Alexia Kagiava, Sarah G. Choudury, Matthew J. Jennings, Lindsay M. Wallace, Allison M. Fowler, Amanda Heslegrave, Jan Richter, Christina Tryfonos, Christina Christodoulou, Henrik Zetterberg, Rita Horvath, Scott Q. Harper, Kleopas A. Kleopa
Journal: Journal of Clinical Investigation (2022)

Charcot-Marie-Tooth disease type 1A (CMT1A), the most common inherited demyelinating peripheral neuropathy, is caused by PMP22 gene duplication. Overexpression of WT PMP22 in Schwann cells destabilizes the myelin sheath, leading to demyelination and ultimately to secondary axonal loss and disability. No treatments currently exist that modify the disease course. The most direct route to CMT1A therapy will involve reducing PMP22 to normal levels. To accomplish this, we developed a gene therapy strategy to reduce PMP22 using artificial miRNAs targeting human PMP22 and mouse Pmp22 mRNAs. Our lead therapeutic miRNA, miR871, was packaged into an adeno-associated virus 9 (AAV9) vector and delivered by lumbar intrathecal injection into C61-het mice, a model of CMT1A. AAV9-miR871 efficiently transduced Schwann cells in C61-het peripheral nerves and reduced human and mouse PMP22 mRNA and protein levels. Treatment at early and late stages of the disease significantly improved multiple functional outcome measures and nerve conduction velocities. Furthermore, myelin pathology in lumbar roots and femoral motor nerves was ameliorated. The treated mice also showed reductions in circulating biomarkers of CMT1A. Taken together, our data demonstrate that AAV9-miR871-driven silencing of PMP22 rescues a CMT1A model and provides proof of principle for treating CMT1A using a translatable gene therapy approach.
mTORC2 mediates structural plasticity in distal nociceptive endings that contributes to pain hypersensitivity following inflammation
Authors: Calvin Wong, Omer Barkai, Feng Wang, Carolina Thörn Perez, Shaya Lev, Weihua Cai, Shannon Tansley, Noosha Yousefpour, Mehdi Hooshmandi, Kevin C. Lister, Mariam Latif, A. Claudio Cuello, Masha Prager-Khoutorsky, Jeffrey S. Mogil, Philippe Séguéla, Yves De Koninck, Alfredo Ribeiro-da-Silva, Alexander M. Binshtok, Arkady Khoutorsky
Journal: Journal of Clinical Investigation (2022)

The encoding of noxious stimuli into action potential firing is largely mediated by nociceptive free nerve endings. Tissue inflammation, by changing the intrinsic properties of the nociceptive endings, leads to nociceptive hyperexcitability and thus to the development of inflammatory pain. Here, we showed that tissue inflammation-induced activation of the mammalian target of rapamycin complex 2 (mTORC2) triggers changes in the architecture of nociceptive terminals and leads to inflammatory pain. Pharmacological activation of mTORC2 induced elongation and branching of nociceptor peripheral endings and caused long-lasting pain hypersensitivity. Conversely, nociceptor-specific deletion of the mTORC2 regulatory protein rapamycin-insensitive companion of mTOR (Rictor) prevented inflammation-induced elongation and branching of cutaneous nociceptive fibers and attenuated inflammatory pain hypersensitivity. Computational modeling demonstrated that mTORC2-mediated structural changes in the nociceptive terminal tree are sufficient to increase the excitability of nociceptors. Targeting mTORC2 using a single injection of antisense oligonucleotide against Rictor provided long-lasting alleviation of inflammatory pain hypersensitivity. Collectively, we showed that tissue inflammation-induced activation of mTORC2 causes structural plasticity of nociceptive free nerve endings in the epidermis and inflammatory hyperalgesia, representing a therapeutic target for inflammatory pain.
Activin-A impairs CD8 T cell-mediated immunity and immune checkpoint therapy response in melanoma
Authors: Katarina Pinjusic, Olivier Andreas Dubey, Olga Egorova, Sina Nassiri, Etienne Meylan, Julien Faget, Daniel Beat Constam
Journal: Journal for ImmunoTherapy of Cancer (2022)

Activin-A, a transforming growth factor β family member, is secreted by many cancer types and is often associated with poor disease prognosis. Previous studies have shown that Activin-A expression can promote cancer progression and reduce the intratumoral frequency of cytotoxic T cells. However, the underlying mechanisms and the significance of Activin-A expression for cancer therapies are unclear.We analyzed the expression of the Activin-A encoding gene INHBA in melanoma patients and the influence of its gain- or loss-of-function on the immune infiltration and growth of BRAF-driven YUMM3.3 and iBIP2 mouse melanoma grafts and in B16 models. Using antibody depletion strategies, we investigated the dependence of Activin-A tumor-promoting effect on different immune cells. Immune-regulatory effects of Activin-A were further characterized in vitro and by an adoptive transfer of T cells. Finally, we assessed INHBA expression in melanoma patients who received immune checkpoint therapy and tested whether it impairs the response in preclinical models.We show that Activin-A secretion by melanoma cells inhibits adaptive antitumor immunity irrespective of BRAF status by inhibiting CD8+ T cell infiltration indirectly and even independently of CD4 T cells, at least in part by attenuating the production of CXCL9/10 by myeloid cells. In addition, we show that Activin-A/INHBA expression correlates with anti-PD1 therapy resistance in melanoma patients and impairs the response to dual anti-cytotoxic T-Lymphocyte associated protein 4/anti-PD1 treatment in preclinical models.Our findings suggest that strategies interfering with Activin-A induced immune-regulation offer new therapeutic opportunities to overcome CD8 T cell exclusion and immunotherapy resistance.
Impact of ski geometry data and standing height ratio on the ACL injury risk and its use for prevention in recreational skiers
Authors: Gerhard Ruedl, Markus Posch, Katja Tecklenburg, Alois Schranz, Klaus Greier, Martin Faulhaber, Irving Scher, Martin Burtscher
Journal: British Journal of Sports Medicine (2022)

To evaluate the impact of ski geometry data and standing height ratio on anterior cruciate ligament (ACL) injury risk of male and female recreational skiers.
Evaluating patterns of co-occurrence between cutaneous and noncutaneous immune-related adverse events after immune checkpoint inhibitor therapy
Authors: Maria S. Asdourian, Nishi Shah, Ted V. Jacoby, Leah L. Thompson, Tracey Otto, Yevgeniy R. Semenov, Kerry L. Reynolds, Steven T. Chen
Journal: Journal of the American Academy of Dermatology (2022)
Natural products as Zika antivirals
Authors: Yuhui Deborah Fong, Justin Jang Hann Chu
Journal: Medicinal Research Reviews (2022)

Abstract Zika virus (ZIKV) is an arbovirus belonging to the flavivirus genus and is transmitted in Aedes mosquito vectors. Since its discovery in humans in 1952 in Uganda, ZIKV has been responsible for many outbreaks in South America, Africa, and Asia. Patients infected with ZIKV are usually asymptomatic; mild symptoms include fever, joint and muscle pain, and fatigue. However, severe infections may have neurological implications, such as Guillain‐Barré syndrome and fetal microcephaly. To date, there are no existing approved therapeutic drugs or vaccines against ZIKV infections; treatments mainly target the symptoms of infection. Preventive measures against mosquito breeding are the main strategy for limiting the spread of the virus. Antiviral drug research for the treatment of ZIKV infection has been rapidly developing, with many drug candidates emerging from drug repurposing studies, and compound screening. In particular, several studies have demonstrated the potential of natural products as antivirals for ZIKV infection. Hence, this paper will review recent advances in natural products in ZIKV antiviral drug discovery.
Tunnel creation method in endoscopic necrosectomy for walled-off pancreatic necrosis
Authors: Kosuke Iwano, Haruka Toyonaga, Tsuyoshi Hayashi, Toshifumi Kin, Akio Katanuma
Journal: Endoscopy (2022)

Walled-off pancreatic necrosis (WON) is one of the most severe complications of acute pancreatitis, and endoscopic necrosectomy may be necessary to treat this complication [1] [2]. When treating a large WON, if only the shallow section is treated, the route to the deepest section may be closed, leaving a space wherein endoscopic necrosectomy cannot be performed [3]. It is important to identify the deepest section of the WON and secure the route by stent placement. Herein, we propose a novel "tunnel creation method" (TCM), which is an endoscopic bougie under fluoroscopy along the stent deployed at the deepest part of the WON that provides a wide working space and a route to the deepest part ([Fig. 1]).
Characterization of Immunopathology and Small Airway Remodeling in Constrictive Bronchiolitis
Authors: Sergey S. Gutor, Bradley W. Richmond, Rui-Hong Du, Pingsheng Wu, Jae Woo Lee, Lorraine B. Ware, Ciara M. Shaver, Sergey V. Novitskiy, Joyce E. Johnson, John H. Newman, Stephen I. Rennard, Robert F. Miller, Timothy S. Blackwell, Vasiliy V. Polosukhin
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

Constrictive bronchiolitis (ConB) is a relatively rare and understudied form of lung disease whose underlying immunopathology remains incompletely defined.
Homologous recombination deficiency (HRD) can predict the therapeutic outcomes of immuno-neoadjuvant therapy in NSCLC patients
Authors: Zhen Zhou, Zhengping Ding, Jie Yuan, Shengping Shen, Hong Jian, Qiang Tan, Yunhai Yang, Zhiwei Chen, Qingquan Luo, Xinghua Cheng, Yongfeng Yu, Xiaomin Niu, Liqiang Qian, Xiaoke Chen, Linping Gu, Ruijun Liu, Shenglin Ma, Jia Huang, Tianxiang Chen, Ziming Li, Wenxiang Ji, Liwei Song, Lan Shen, Long Jiang, Zicheng Yu, Chao Zhang, Zaixian Tai, Changxi Wang, Rongrong Chen, David P. Carbone, Xuefeng Xia, Shun Lu
Journal: Journal of Hematology & Oncology (2022)

Abstract Background Neoadjuvant immunotherapy is emerging as novel effective intervention in lung cancer, but study to unearth effective surrogates indicating its therapeutic outcomes is limited. We investigated the genetic changes between non-small cell lung cancer (NSCLC) patients with varied response to neoadjuvant immunotherapy and discovered highly potential biomarkers with indicative capability in predicting outcomes. Methods In this study, 3 adenocarcinoma and 11 squamous cell carcinoma NSCLC patients were treated by neoadjuvant immunotherapy with variated regimens followed by surgical resection. Treatment-naive FFPE or fresh tissues and blood samples were subjected to whole-exome sequencing (WES). Genetic alternations were compared between differently-responded patients. Findings were further validated in multiple public cohorts. Results DNA damage repair (DDR)-related InDel signatures and DDR-related gene mutations were enriched in better-responded patients, i.e., major pathological response (MPR) group. Besides, MPR patients exhibited provoked genome instability and unique homologous recombination deficiency (HRD) events. By further inspecting alternation status of homology-dependent recombination (HR) pathway genes, the clonal alternations were exclusively enriched in MPR group. Additionally, associations between HR gene alternations, percentage of viable tumor cells and HRD event were identified, which orchestrated tumor mutational burden (TMB), mutational intratumor heterogeneity (ITH), somatic copy number alteration (SCNA) ITH and clonal neoantigen load in patients. Validations in public cohorts further supported the generality of our findings. Conclusions We reported for the first time the association between HRD event and enhanced neoadjuvant immunotherapy response in lung cancer. The power of HRD event in patient therapeutic stratification persisted in multifaceted public cohorts. We propose that HR pathway gene status could serve as novel and additional indicators guiding immune-neoadjuvant and immunotherapy treatment decisions for NSCLC patients.
Update on Biology and Genomics of Adrenocortical Carcinomas: Rationale for Emerging Therapies
Authors: Antonio Marcondes Lerario, Dipika R Mohan, Gary D Hammer
Journal: Endocrine Reviews (2022)

The adrenal glands are paired endocrine organs that produce steroid hormones and catecholamines required for life. Adrenocortical carcinoma (ACC) is a rare and often fatal cancer of the peripheral domain of the gland, the adrenal cortex. Recent research in adrenal development, homeostasis, and disease have refined our understanding of the cellular and molecular programs controlling cortical growth and renewal, uncovering crucial clues into how physiologic programs are hijacked in early and late stages of malignant neoplasia. Alongside these studies, genome-wide approaches to examine adrenocortical tumors have transformed our understanding of ACC biology, and revealed that ACC is composed of distinct molecular subtypes associated with favorable, intermediate, and dismal clinical outcomes. The homogeneous transcriptional and epigenetic programs prevailing in each ACC subtype suggest likely susceptibility to any of a plethora of existing and novel targeted agents, with the caveat that therapeutic response may ultimately be limited by cancer cell plasticity. Despite enormous biomedical research advances in the last decade, the only potentially curative therapy for ACC to date is primary surgical resection, and up to 75% of patients will develop metastatic disease refractory to standard-of-care adjuvant mitotane and cytotoxic chemotherapy. A comprehensive, integrated, and current bench-to-bedside understanding of our field's investigations into adrenocortical physiology and neoplasia is crucial to developing novel clinical tools and approaches to equip the one-in-a-million patient fighting this devastating disease.
EZH2 inhibitor tazemetostat in patients with relapsed or refractory, BAP1-inactivated malignant pleural mesothelioma: a multicentre, open-label, phase 2 study
Authors: Marjorie G Zauderer, Peter W Szlosarek, Sylvestre Le Moulec, Sanjay Popat, Paul Taylor, David Planchard, Arnaud Scherpereel, Marianna Koczywas, Martin Forster, Robert B Cameron, Tobias Peikert, Evren Kocabaş Argon, Neil R Michaud, Attila Szanto, Jay Yang, Yingxue Chen, Vikram Kansra, Shefali Agarwal, Dean A Fennell
Journal: The Lancet Oncology (2022)
Molecular profiling and clinical implications of patients with acute myeloid leukemia and extramedullary manifestations
Authors: Jan-Niklas Eckardt, Friedrich Stölzel, Desiree Kunadt, Christoph Röllig, Sebastian Stasik, Lisa Wagenführ, Korinna Jöhrens, Friederike Kuithan, Alwin Krämer, Sebastian Scholl, Andreas Hochhaus, Martina Crysandt, Tim H. Brümmendorf, Ralph Naumann, Björn Steffen, Volker Kunzmann, Hermann Einsele, Markus Schaich, Andreas Burchert, Andreas Neubauer, Kerstin Schäfer-Eckart, Christoph Schliemann, Stefan W. Krause, Regina Herbst, Mathias Hänel, Maher Hanoun, Ulrich Kaiser, Martin Kaufmann, Zdenek Rácil, Jiri Mayer, Frank Kroschinsky, Wolfgang E. Berdel, Gerhard Ehninger, Hubert Serve, Carsten Müller-Tidow, Uwe Platzbecker, Claudia D. Baldus, Johannes Schetelig, Martin Bornhäuser, Christian Thiede, Jan Moritz Middeke
Journal: Journal of Hematology & Oncology (2022)

Abstract Background Extramedullary manifestations (EM) are rare in acute myeloid leukemia (AML) and their impact on clinical outcomes is controversially discussed. Methods We retrospectively analyzed a large multi-center cohort of 1583 newly diagnosed AML patients, of whom 225 (14.21%) had EM. Results AML patients with EM presented with significantly higher counts of white blood cells ( p &lt; 0.0001), peripheral blood blasts ( p &lt; 0.0001), bone marrow blasts ( p = 0.019), and LDH ( p &lt; 0.0001). Regarding molecular genetics, EM AML was associated with mutations of NPM1 (OR: 1.66, p &lt; 0.001), FLT3 -ITD (OR: 1.72, p &lt; 0.001) and PTPN11 (OR: 2.46, p &lt; 0.001). With regard to clinical outcomes, EM AML patients were less likely to achieve complete remissions (OR: 0.62, p = 0.004), and had a higher early death rate (OR: 2.23, p = 0.003). Multivariable analysis revealed EM as an independent risk factor for reduced overall survival (hazard ratio [HR]: 1.43, p &lt; 0.001), however, for patients who received allogeneic hematopoietic cell transplantation (HCT) survival did not differ. For patients bearing EM AML, multivariable analysis unveiled mutated TP53 and IKZF1 as independent risk factors for reduced event-free (HR: 4.45, p &lt; 0.001, and HR: 2.05, p = 0.044, respectively) and overall survival (HR: 2.48, p = 0.026, and HR: 2.63, p = 0.008, respectively). Conclusion Our analysis represents one of the largest cohorts of EM AML and establishes key molecular markers linked to EM, providing new evidence that EM is associated with adverse risk in AML and may warrant allogeneic HCT in eligible patients with EM.
5-hydroxytryptamine produced by enteric serotonergic neurons initiates colorectal cancer stem cell self-renewal and tumorigenesis
Authors: Pingping Zhu, Tiankun Lu, Zhenzhen Chen, Benyu Liu, Dongdong Fan, Chong Li, Jiayi Wu, Luyun He, Xiaoxiao Zhu, Ying Du, Yong Tian, Zusen Fan
Journal: Neuron (2022)
How I approach smoldering multiple myeloma
Authors: Iuliana Vaxman, Morie A. Gertz
Journal: Blood (2022)

The current standard of care in smoldering multiple myeloma (SMM) is close surveillance, outside of clinical trials. Efforts are being made to understand the pathobiologic process that leads to the progression of SMM to active MM. This review provides a critical description of available data, including risk factors and risk models of progression, as well as clinical trials investigating interventions for this patient population. We describe 2 cases in which patients were seen before the concept of a myeloma-defining event was established. Today, based on the International Myeloma Working Group criteria, both patients would have been identified as experiencing myeloma-defining events, and therapy would have been initiated. These cases show that occasionally, patients can undergo observation only, even when they exceed criteria for high-risk SMM.
Evaluation of Inference-Based Cognitive-Behavioral Therapy for Obsessive-Compulsive Disorder: A Multicenter Randomized Controlled Trial with Three Treatment Modalities
Authors: Frederick Aardema, Stéphane Bouchard, Diana Koszycki, Marc E. Lavoie, Jean-Sebastien Audet, Kieron O’Connor
Journal: Psychotherapy and Psychosomatics (2022)

&lt;b&gt;&lt;i&gt;Introduction:&lt;/i&gt;&lt;/b&gt; Inference-based cognitive-behavioral therapy (I-CBT) is a specialized psychological treatment for obsessive-compulsive disorder (OCD) without deliberate and prolonged exposure and response prevention (ERP) that focuses on strengthening reality-based reasoning and correcting the dysfunctional reasoning giving rise to erroneous obsessional doubts and ideas. &lt;b&gt;&lt;i&gt;Objective:&lt;/i&gt;&lt;/b&gt; The present study aimed to evaluate the effectiveness of I-CBT through a comparison with appraisal-based cognitive behavioral therapy (A-CBT) and an adapted mindfulness-based stress reduction (MBSR) intervention. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; This was a two-site, parallel-arm randomized controlled trial (RCT) comparing I-CBT with A-CBT. The MBSR intervention acted as a non-specific active control condition. Following formal evaluation, 111 participants diagnosed with OCD were randomly assigned. The principal outcome measure was the Yale-Brown Obsessive-Compulsive Scale. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; All treatments significantly reduced general OCD severity and specific symptom dimensions without a significant difference between treatments. I-CBT was associated with significant reductions in all symptom dimensions at post-test. Also, I-CBT led to significantly greater improvement in overvalued ideation, as well as significantly higher rates of remission as compared to MBSR at mid-test. &lt;b&gt;&lt;i&gt;Conclusions:&lt;/i&gt;&lt;/b&gt; I-CBT and MBSR appear to be effective, alternative treatment options for those with OCD that yield similar outcomes as A-CBT. I-CBT may have an edge in terms of the rapidity by which patients reach remission, its generalizability across symptom dimension, its potentially higher level of acceptability, and effectiveness for overvalued ideation. Future research is needed to assess whether additional alternative treatments options can help to increase the number of people successfully treated.
Abstract IA008: Charting normal and malignant differentiation topologies with single-cell multi-omics
Authors: Dan Landau
Journal: Cancer Research (2022)

Abstract Somatic evolution is a novel emerging frontier in human biology, as cells within diverse normal and malignant tissues have been shown to diversify and undergo selection. We and others have shown that somatic evolution is driven by both genetic and non-genetic modes of inheritance (Cell, 2013; Cancer Cell, 2014; Nature, 2015; Nature Communications 2016 &amp; 2019; Cell Systems, 2019). A key challenge is to integrate across these different layers of information at the level of the single cell – the atomic unit of the evolutionary process (Nature Reviews Genetics, 2020). To address this challenge, we have developed single-cell multi-omics technologies and analytical frameworks to link genetic, epigenetic and phenotypic information (Nature, 2019a &amp; Nature, 2019b). We have applied these methods to chart how somatic mutations reshape the differentiation topographies of neoplastic and normal hematopoiesis (Nature, 2019a; Nature Genetics, 2020), as well as defined the epigenetic encoding, inheritance, and plasticity of malignant transcriptional cell states (Nature, 2019b; Nature Genetics, 2021). Citation Format: Dan Landau. Charting normal and malignant differentiation topologies with single-cell multi-omics [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr IA008.
Painful Erythematous Plaques on the Trunk
Authors: Byeong Chang Ko, Hai-Jin Park, Mira Choi
Journal: JAMA Dermatology (2022)

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